1
Lessons from Neurobiology: Understanding the Overlap between Pain and Mood Disorders
Rakesh Jain, MD, MPH
R/D Clinical Research, Inc.Lake Jackson, Texas, USATexas Tech Health Sciences Center – Permian BasinMidland, Texas, USA
Let’s Ask (and Answer) Three Questions
1. Is there a link between chronic pain and depression
2. Why is there a link between chronic pain and depression?
3. What do we do about this chronic pain and depression link?
2
3
1. Is there a link between Chronic Pain and Depression
Lifetime Prevalence of Mental Illnesses is High
14.6%
20.8%24.8%
28.8%
0%
10%
20%
30%
40%
50%
Substance UseD/O
Mood D/O Impulse ControlD/O
Anxiety D/O
Risk of any disorder: 46.4 %2 or more disorder: 27.7 %3 or more disorders: 17.3 %
Kessler RC, et al. Arch Gen Psychiatry. 2005;62:593-602. 4
Is Pain Impacted by the Co-occurrence of Psychiatric Disorders?
Pain Severity Pain Interference0
1
2
3
4
5
6
7
8
Pain only Pain and Anxiety Pain and Depression Pain, Depression and Anxiety
Bri
ef P
ain
In
ven
tory
Pai
n S
core
(m
ean
)ra
ng
e:
0-1
0
**
*
*
**
*P<0.001
Bair MJ, et al. Psychosom Med. 2008;70:890-897. 5
6
Pain Condition (Headaches) and Depression/Anxiety
Major De-pression
Panic D/O Generalized Anxiety D/O
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
1.0 1.0 1.0
2.84
3.293.03
n=15,330 - without HAs n= 3,045 - with headaches
Adj
uste
d od
ds ra
tio
Weighted 12 month adjusted odds ratio of association between severe headaches or migraine and mental disorders
Adjusted odds ratio (adjusted for age, race, sex, and educational status).Kalaydjain A, Merikangas K. Psychosom Med. 2008;70:773-780.
*P<0.05
*
**
“Ring of Fire”: Odds Ratio of Psychiatric Comorbidities in Fibromyalgia
Fibromyalgia
Any Anxiety Disorder
6.7
Eating Disorder
2.4
Substance Use Disorder
3.3
Major Depression
2.7
Arnold LM, et al. J Clin Psychiatry. 2006;67:1219-1225. 7
6.1
7.9
10.3
6.7
8.9
11.0
Mild Moderate Severe
HADS - depression score
HADS - anxiety score
BPI – DPN Average Pain Severity
Mea
n s
core
DPNP Patients: Relationship Between Pain and Mental Disorders
**
**
*P<0.01
Gore M, et al. J Pain Symptom Manage. 2005;30(4):374-385. 8
2.0
4.6*
3.1
5.4*
No Painn=50
Chronic Painn=40
Me
an
sc
ore
HADS-depression score
HADS-anxiety score
(HADS-Depression score)*P<0.05 • 3 years later: 45% had
chronic pain
• 3 years after accident: 4.4% developed PTSD
• >10% developed subsyndromal PTSD
• All but one patient with PTSD (full or sub-syndromic) had chronic pain
Chronic Pain After Accidental Injury and its Relationship to Depression and Anxiety
Jenewein J, et al. J Psychosom Res. 2009;66:119-126. 9
5.95
7.92
10.16
0
2
4
6
8
10
12
NPAD-d in lowestquartile
NPAD-d in middlequartiles
NPAD-d in highestquartile
HA
DS
An
xiet
y S
ub
-sca
le M
ean
S
core
s (
s sc
ore
ran
ge
0–21
)
*P<0.001
Dose-Response Curve Exists Between Chronic Pain and Psychiatric Difficulties
*
*
N=448.HADS=Hospital Anxiety and Depression Scale; NPAD-d=Neck Pain and Disability Scale German Version.Blozik E, et al. BMC Musculoskelet Disord. 2009;10(13):1-8. 10
Do Anxiety, Depression, or Sleep Problems Predict the Development of Pain?
15 month prospective study, 3171 followed, 324 developed chronic widespread pain
score 0 - 4 score 5 - 7 score 8 -21
11.4
2.6
Anxiety (HAD Anxiety sub-score)
Od
ds
Ra
tio
score 0 - 2 score 3 - 5 score 6 -20
1
1.8
2.9
Depression (HAD Depression sub-score)
Od
ds
Rati
o
score 0 - 3 score 4 - 8 score 9 -20
1
2
3.4
Sleep (Sleep Problem Scale)
Od
ds
Rati
o
Gupta A, et al. Rheumatology. 2007;46:666-671. 11
In Conclusion to Question 1:
Is there a link between Chronic Pain and Depression?
Answer: Yes! And it’s a strong link…
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2. Why is there a link between chronic pain and depression?
The Pain Circuit Involves Sensory, Emotional, and Cognitive Regions of the Brain
Fast, myelinate
d A-fibers
Slow, unmyelinated C-fibers
Somatosensory cortex
Thalamus
Limbic system
CerebrumBrainstem
Spinal cordSpinothalamic tract
Dorsalganglion
Afferent nerve fiber
Adapted from Giordano J. Pain Physician. 2005;8:277-290. 14
The “Pain Matrix”
A=amygdala; ACC=anterior cingulate cortex; Cer=cerebellum; H=hypothalamus; Ins=insula; l, m=lateral and medial thalamus; M1=primary motor cortex; NA=nucleus accumbens; PAG=periaqueductal gray; PFC=prefrontal cortex; PPC=posterior parietal cortex; S1, S2=primary and secondary somatosensory cortex; SMA=supplementary motor area.
Sensory-Motor RegionsPrimary sensory and motor corticesThalamusPosterior insula
Emotional/Affective RegionsAnterior cingulate AccumbensPosterior cingulate Hippocampus Orbitofrontal cortex ThalamusMedial prefrontal cortex AmygdalaAnterior insula Caudate
Cognitive/Integrative RegionsPrefrontal cortexTemporal lobeParietal cortex
Modulatory RegionsMidbrain (PAG, NCu) Cortical regionsPaphe nucleus Subcortical regions
Regi
onal
Inte
racti
ons
Borsook D, et al. Neuroscientist. 2010;16(2):171-185. 15
A Closer Look at Shared Anatomy: Complex Circuits Involve Sensory, Cognitive, and Emotional Regions
Apkarian AV, et al. Eur J Pain. 2005;9:463-484. 16
Negative Emotions Robustly Increased Pain and Autonomic Response
Change in Emotion (Emotion-Baseline)
Cha
nge
in P
ain/
Unp
leas
antn
ess
(Em
otio
n B
asel
ine)
RelaxationSadnessAngerFear and AnxietyReliefSatisfaction –50.0
50.0
100.0
–100.0
–20.0 –10.0
20.010.0
R2=0.57
(Emotions hypnotically induced)
N=26.Rainville P, et al. Pain 2005;118:306-318. 17
CORTICO-LIMBIC INPUT
PAGOPIOIDS
RMCNE
DLF
NRM5-HT
SPINAL INTER-
NEURON
MIDBRAINBRAINSTREAM
Primary nociceptive
afferents
(+)
(+)
(-)
(+)
(+)
(+)
(-)(-)
(-)
PSTT
GABAINTER-
NEURON
Many Neurotransmitters are Shared by Pain and Depression
(+)
5-HT=5-hydroxytryptamine; DLF=dorolateral funiculus; NRM=nucleus raphe mangus; RMC=reticular magnocellular nuclei; PAG=periaqueductal grey substance; PSTT=paleospinothalic tract. Giordano J. Pain Physician 2005;8:277–90. 18
Pain and Depression: a Deeper Examination
• Focus on:– HPA– Inflammatory cytokines – Autonomic nervous system
HPA=hypothalamic-pituitary axis. 19
Shared Neuroendocrine and Neuroimmune Dysregulation
Red = inhibitory pathway
Green = stimulatory pathway
1. Raison CL, et al. Trends Immunol. 2006;27:24-31. 2. Nestler EJ, et al. Neuron. 2002;34:13-25. 3. Blackburn-Munro G, Blackburn-Munro RE. J Neuroendocrinol. 2001;13:1009-1023. 20
Stress/Inflammation Link: a True Mind-Body (and Circular) Relationship
CRH=corticotropin-releasing hormone; NF-κB=nuclear factor kappa B; ACTH=adrenocorticotropic hormone.Miller AH, et al. Biol Psychiatry. 2009;65:732-741. 21
Autonomic Dysregulation May Augment Pain
P <.05
P <.05
P =NS
n=20
n=20n=20
Norepinephrine-evoked pain
-2
-1
0
1
2
3
4
5
6
7
8
9
10
FM RA HC
(nor
epin
eph
rine-
pla
cebo
)
0
20
40
60
80
100
30.0 30.0
Pa
tie
nts
(%
)
n=20
n=20 n=20
P≤0.05
P=NS
16/20 6/20 6/20
56.3%
94.3%
54.3%
11.9%
54.3%
11.9%
Vis
ual a
nalo
g s
cale
Martinez-Lavin M, et al. BMC Musculoskelet Disord. 2002;3:2. 22
A Comprehensive, Neurobiological View of Pain and Psychology
Jain R, et al. Curr Diab Rep. 2011;11:275-284. 23
Potential Clinical Consequences of Relationship of Pain to HPA, Pro-inflammatory Cytokines, and the Autonomic System
Potential consequences of such dysregulation:• Fatigue• Sleep impairment• Depressed mood and anhedonia• Difficulty concentrating • Anxiety and irritability• Appetite and libido disturbances
Pain
AutonomicNervous System
Cytokines
Kim YK, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1044-1053. Raison CL, et al. CNS Drugs. 2005;19:105-123. Dantzer R. Neurol Clin. 2006;24:441-460. 24
How Pain and Psychiatric Difficulties Get Tied Together by Neurobiology
Tracey I, Dickenson T. Cell. 2012;148:1308-1308, e2 . 25
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And the consequences of this overlap are …
Immunologic Impact of Pain With Increasing Duration of Pain
• IL-8 is a proinflammatory cytokine, mediates sympathetic pain
• IL-Ra is involved with stress • IL-6 is involved with stress, fatigue, hyperalgesia, depression,
and it activates sympathetic pain
Substance P Increased sympathetic activity
Hyperalgesia, fatigue, depression
Sympathetic mediated pain
IL-6
IL-8
IL-IRa
Catechols, Neurokinin K
<2-yr symptoms >2-yr symptoms0
75
150
225
300
375
450
525
600
675
750
Serum IL-8 Serum IL-Ra Serum IL-6
pg
/mL
n=23 n=23
**P<0.001
*
Patients met ACR criteria for FM.Wallace DJ, et al. Rheumatology. 2001:40:743-749. Schwartz YA, et al. Am J Resp Cell Mol Biol. 1999;21:388-394. 27
Patients with chronic back pain (CBP) had 5%–11% less whole brain gray matter, equivalent to 10–20 years of normal aging
Back Pain Patients may Experience Gray Matter Atrophy in Areas Involved With Cognition and Emotional Regulation
Apkarian AV et al. J Neurosci. 2004;24(46):P10410-P10415. 28
GM Loss in Pain – in Regions Also Involved With Anxiety Regulation
0
400,000
800,000
1,200,000
1,600,000
GM WM CSF Total Volume
HC FM
*P <0.001
Vo
lum
e (m
m3 )
• Patients with FM (n=10) had significantly less GM volume in posterior cingulate, insular cortex, MFC, and parahippocampal gyrus
• Rate of age-related decline was significantly greater in patients with FM than in controls (n=10; P<0.001)
• Patients with FM were losing 10.5 cm3 of GM annually since year of their diagnosis
*
*
C=controls; CSF=cerebrospinal fluid; GM=grey matter; WM=white matter; MFC=medical frontal cortex.Kuchinad A, et al. J Neurosci. 2007;27:4004–4007. 29
FM – AD = 29 FM + AD = 29
HC = 29
R = –0.47P<0.002
Pain and Brain Volume Changes When Comorbid with Depression or Anxiety
GMV=gray matter volume; TIV=total intracranial volume; STPI=State-Trait Personality InventoryHsu MC, et al. Pain. 2009;143(3):262-267. 30
Chronic Pain (Low Back Pain) Impacts the Brain (Same Regions Shared With Mood/Anxiety Control)
• Cortical thickness in CLBP patients (n=18) compared with controls (n=16)
• Random-field theory-based cluster-corrected P<0.05 maps
• Blue areas represent clusters that are significantly thinner in CLBP patients than controls
Seminowicz DA, et al. J Neurosci. 2011;31(20):7540-7550. 31
In Conclusion to Question 2:
Why is there a link between chronic pain and depression?
Answer: For multiple reasons:• Shared anatomy• Shared chemistry• Shared pathways that connect the mind and body, are a
few reasons for such a link
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3. What do we do about this chronic pain and depression link?
First: We use Neurobiology to Understand our Treatment Options
Tracey I, Dickenson T. Cell. 2012;148:1308-1308, e2 . 34
Recommendations from the British Pain Society
Experts from the BPS Consensus Guidelines in Pain Management in Adults
• “Pain management programmes based on cognitive behavioural principles, are the treatment of choice…”
• “Evaluation of outcomes should be standard practice, assessing distress/emotional impact of pain…”
BPS Recommended Guidelines for Pain Management Programmes for Adults, Consensus Statement, April 2007. 35
7.1
41.2
6.1*
38.2*
5.6*
31.9*
5.7*
34.9*
Average Pain (0-10 scale) n=18 Pain-related Anxiety (Pass-20)n=20
Pre-treatment
Post-treatment
3 month Follow-up
6 month Follow-up
N=41; data for individuals completing 6-month follow-up
*P<0.05
• Six weekly 90-minute group sessions
• Based on CBT Attention management manual
*
Cognitive Behavioral Management of Chronic Pain
Elomaa MM, et al. Eur J Pain. 2009;13(10):1062-1067. 36
0.37
0.91
-0.88
-1.50
-0.64
-1.21
Depression Anxiety Pain Interference
Worsening
Improvement
Comparison group n=37
Intervention group n=41
Change from Baseline Scores
CES-D STAI BPI-Interference
Mind-Body Intervention for Older Adults with Chronic Pain
Berman RLH, et al. J Pain. 2009;10(1):68-79. 37
Long-term Benefits of Psychotherapy in FM (12-Month Follow-up Data)
% of Patients Reporting -60 -40 -20 0 20 40 60
AttentionPlacebo (AP)
Operant Behavioral Therapy (OBT)
Cognitive Behavioral Therapy (CBT)
Clinically significant reduction in pain
Clinically significant increase in pain
N=125: CBT: n=42; OBT: n=43; AP: n=40.Thieme K, et al. Arthritis Rheum. 2007;57(5):830-836. 38
• Psychoeducation
• Relaxation training
• Behavioral pacing
• Relapse prevention
• Realistic goal setting
• Identifying dysfunctional thought patterns
• Communication skills training
Key Elements of Cognitive Behavioral Therapy
Bennett R, et al. Nat Clin Pract Rheumatol. 2006;2(8):416-424. 39
Physical Fitness in Individuals With Chronic Pain
In physical self-report or functional testing, the average 40-year-old patient who has FM was found to be as physically unfit as an 80-year-old person who does not have FM
Rutledge DN, et al. J Nurs Scholarsh. 2007;39(4):319-324. Shillam CR, et al. Arthritis Rheum. 2009;58(suppl 9):1408. 40
Top 10 Principles for Prescribing Exercise
• Treat peripheral pain generators to minimize central sensitization
• Minimize eccentric muscle work
• Program low-intensity nonrepetitive exercise
• Recognize importance of restorative sleep
• Screen for and treat autonomic dysfunction
• Evaluate for poor balance and risks for falling
• Modify exercise for common comorbidities
• Address obesity and deconditioning
• Conserve energy in daily life to exercise
• Promote self-efficacy
Jones KD, et al. Rheum Dis Clin N Am. 2009;35(2):373-391. 41
Aerobic Performance
Tender Point Pain Pressure Threshold
Improvement in Pain
Improvement (%)Worsening (%)
-1.6
-7.0
0.5
11.4
28.1
17.1
Control group
Exercise intervention group
Exercise: a Meta-analysis of Studies
0
Busch AJ, et al. Cochrane Database Syst Rev. 2002;(3):CD003786. 42
CBT: How Effective Is It? For Which Symptoms of FM Is It Effective?
A total of 14 out of 27 RCTs with 910 subjects with a median treatment time of 27 hours (range: 6-75) over a median of 9 weeks (range: 5-15) were included
“ . . . the high grade of recommendation given to CBT in the American and German guidelines on FM needs to be reconsidered”
Pain (13/664)
Fatigue (4/200)
Sleep (4/141)
Depressed mood (12/631)
-0.24(P=0.10)
0.05(P=0.71)
-0.15(P=0.50)
-0.24(P=0.004)
Outcome (# Study Arms/# Patients)
Effect Size
Bernardy K, et al. J Rheumatol. 2010;37(10):1991-1205. 43
Tai Chi in Chronic Pain: Demonstrated Effectiveness of a Mind-Body Intervention
Tai Chi group, n=33Control group, n= 33
12 weeks, twice weekly, 60-minute Tai Chi sessions vs
wellness education and stretching
FIQ = FM impact questionnaire.
FIQ at 12 weeks (P<0.001)Improvements were maintained at
24 weeks (P<0.001)
Chenchen W, et al. N Engl J Med. 2010;363(8):743-754. 44
• Relationship between self-reported FM severity and current pain (A) and pain-related sleep interference (B)
• Values represent mean scores from short form of modified Brief Pain Inventory
• P-values are for overall association between FM severity and levels of current pain and pain-related sleep interference using ANOVA
Relationship Between Pain, Pain Severity, and Sleep
Silverman S, et al. BMC Musculoskelet Disord. 2010;11:66. 45
Pharmacological Treatment Options forAnxiety and Mood Disorders
• Gabapentin • Pregabalin
• Fluoxetine• Sertraline• Paroxetine• Citalopram• Escitalopram
• Lorazepam• Clonazepam• Alprazolam
Benzos SSRIs
α 2 δ ligandsSNRIs• TCAs (many)
• Venlafaxine• Duloxetine• Desvenlafaxine• milnacipran
46
3 weeks of multidisciplinary treatment consisted of education, stretching, CBT, relaxation training, and aerobic exercise
Multidisciplinary Treatment: Impact on Improvement and HPA Changes
N=12.CBT=cognitive behavioral therapy; CES-D=Center for Epidemiologic Studies Depression Rating Scale.Bonifazi M, et al. Psychoneuroendocrinology. 2006;31:1076-1086.
Before admission and treatment
Before treatment
After treatment
64.1
57.3
22.4
5.5
48.9
38
13.3
63.1
24.9
69
13.5
13.3
VASScore
(1-100)
% of Pain Area
CES-DScore(0-60)
*
*
*
*
*P<0.05
Positive Tender
Points (n)
47
If Treatment of Pain Succeeds, Then There is Positive Impact on the Brain – This is Good News Indeed!
t- and p-value maps for patients who responded to treatment (n=11) showing that the left DLPFC became thicker in patients after
treatment compared with before treatment (arrow)
Seminowicz DA, et al. J Neurosci. 2011;31(20):7540-7550. 48
A Suggested Clinical Pathway to Managing Depression in a Patient with Pain
Routinely Screen for
Anxiety D/Os
Use Scales/Screeners
Optimize Treatment of
Pain
If Anxiety still persists
Non-pharmacological
treatment(s)
Pharmacological treatment(s)
49
Scales for Diagnosing Anxiety and Depression
HADS PHQ-9
GAD-7
50
A Clinically Useful Anxiety Screener: GAD-7
Kroenke K, et al. Ann Intern Med. 2007;146:317-325. 51
0.92
0.820.78 0.760.76 0.75 0.74 0.75
Generalized AnxietyD/O
PanicD/O
Social Anxiety D/O PTSD
Sensitivity
SpecificityGAD-7 Score of ≥8
GAD-7: Useful in Detecting Multiple Anxiety Disorders
Kroenke K, et al. Ann Intern Med. 2007;146:317-325. 52
GAD-7
How to Use
• Patients circle one of the 4 numbers (representing severity) associated with 7 problems
• If patients identify any problems, they then indicate (by checking the appropriate box) the degree to which these problems made it difficult for them to work, take care of home responsibilities, or get along with people
53
How to Use• Brief, 9-item self-report
screening tool to help identify symptoms that could relate to depression
• Developed for use in primary care settings
PHQ-9
54
PHQ-9
How to Score Major depressive syndrome is suggested if: • Of the 9 items, 5 or more are circled as at least “More than half the days”• Either item 1a or 1b is positive, that is, at least “More than half the days”
Minor depressive syndrome is suggested if: • Of the 9 items, b, c, or d are circled as at least “More than half the days” • Either item 1a or 1b is positive, that is, at least “More than half the days”
Add all circled answers. For every answer circled:
Not at all = 0
Several Days = 1
More than half the days = 2
Nearly every day = 3
Total Score Depression Severity
0-4 None
5-9 Mild
10-14 Moderate
15-19 Moderately Severe
20-27 Severe
Pfizer Inc. Instructions for Use (for doctor or healthcare professional use only): PHQ-9 Quick Depression Assessment. Available at: http://www.phqscreeners.com/pdfs/PHQ9InstruxforUse.pdf.; The MacArthur Initiative on Depression and Primary Care at Dartmouth and Duke. Depression Management Tool Kit. Hanover, NH: Trustees of Dartmouth College, 2004. 55
56
In Conclusion:
Optimum would be early, full, and sustained control over ALL symptoms
Pain
Sleep
Fatigue
Cognitive
Metabolic
57
What Are We Treating When We “Treat” a Patient ?
Cognitive disturbanceFatigue
Sleep disturbance
PainMetabolic syndrome
58
Educate, educate, educate Reassure, reassure,
reassure Start slow, go slow titration
schedule “Off-label” titration often
employed and often appropriate
Aggressively manage early adverse effects
Pseudo or false failure of medication trials is common
It is because of several reasons patients appear to be unusually sensitive to medication adverse effects
Catastrophizing is a known psychological trait of patients
We clinicians often tend to start patients on too aggressive a titration schedule
Encountering, and Conquering “Pseudo-medication” Failure
SolutionProblem
59
Target Symptoms and Shared Neurobiology of Chronic Pain and Depression
Genetic predisposition
Neuroendocrine- immune
dysfunction
CSS
ANS dysfunctionPoor sleep
Trauma Psychological factors, stress
Infections, Inflammation
Neonatal, Childhood trauma
Otherfactors
Hyperexcitement of central neurons Environmental,
ChemicalCentral
sensitization
Central sensitization
Other mechanisms
Yunus MB. Semin Arthritis Rheum. 2007;36:339-356. 60
Four Things to Keep in Mind
1. “Abnormal” psychological problems – such as anxiety and depression, are very common in pain conditions
2. This creates a bi-directional, “spiral down” negative impact on the pain patient
3. Multiple links exist between pain and psychological issues – neuro-endocrine, neuro-inflammation, autonomic disruptions, etc
4. Treatment – Pain outcomes are negatively impacted if psychological issues are not well identified (thankfully, reverse is equally true!)
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